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Brain regeneration requires the coordination of complex responses in a time- and region-specific manner

September 2, 2022, Hangzhou BGI Life Sciences Research Institute, Shenzhen BGI Life Sciences Research Institute, Qingdao BGI Genetics Research Institute, Guangdong Provincial People's Hospital, South China Normal University, Wuhan University, University of Chinese Academy of Sciences School of Life Sciences, Shenzhen Bay Laboratory, Whitehead Institute of Biomedical Research in the United States, University of Copenhagen in Denmark and other 17 units from China, the United States, and Denmark cooperated with 17 units.

Here, we identify an injury-induced cluster of ependymal glial cells at the wound site as a potential population of progenitor cells to replenish lost neurons through a cellular state transition process similar to neurogenesis during development

Mammals face challenges in recovering from brain injury due to their limited regenerative capacity
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By contrast, lower vertebrates such as bony fish and salamanders exhibit regenerative abilities
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Forebrain regeneration in salamanders was first observed in larvae and later in adults
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Cortical cell types lost in the salamander telencephalon can apparently be recovered after injury
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Therefore, salamanders can serve as models to study brain regeneration, potentially leading to valuable discoveries that are valuable for understanding the inherent limitations of mammalian brain regeneration and ultimately for developing regenerative medicine for the central nervous system
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Previous studies in various regenerative species have shown that ependymal glial cells (EGCs), comparable to neural stem cells in mammals, contribute to neurogenesis during brain regeneration
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Salamander EGCs may give rise to nearly all cell types in the brain during development
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Unlike mammals, where neural stem cells are almost depleted once brain development is complete, with the exception of those in the subventricular zone and the dentate gyrus of the hippocampus, adult salamanders contain dividing EGCs in the brain
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EGCs are distributed throughout the ventricular zone (VZ) of the adult salamander brain and in several restricted regions of the VZ in erythematosus salamanders
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The erythematous salamander has been reported to contain two groups of EGCs: slowly dividing and transiently amplified EGCs
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The first group was stem-like, expressing glial fibrillary acidic protein (GFAP) and glutamine synthase, and exhibiting long-term retention of 5-bromo-2′-deoxyuridine (BrdU) stem cell properties
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The second group is located within the proliferation hotspot of the VZ and divides frequently
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Both EGC groups responded to injury and expanded to larger areas of the cerebral cortex
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Science cover article (image courtesy of Science) So far, the role and regulation of EGCs in regeneration has only been partially characterized
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Several signaling pathways for EGC activation and brain regeneration, such as Notch, FGF, and Gata3, have been documented in salamanders and fish; these are also implicated in brain development, suggesting that brain regeneration and development may have similar molecular regulation
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However, it is unclear whether and to what extent brain regeneration recapitulates embryonic development
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Therefore, more systematic characterization of cellular and molecular functions is required to confirm the mechanistic understanding of brain regeneration
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Several spatial transcriptomic techniques suitable for dissecting developmental and tissue regeneration processes have been developed to resolve gene expression profiles of cells in situ
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Using these methods, in situ transcriptomic profiles of mouse brain or human cortex have been resolved at 100 and 55 μm resolution, respectively, which reflect the average expression profile of a group of adjacent cells
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Given the complexity of brain structures and cell types, there is a need to improve the resolution of transcript capture to improve the accuracy of data interpretation
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Sequence fluorescence in situ hybridization (FISH) and multiplexed error-resistant FISH were developed to analyze gene expression in single cells, but their application is limited by low throughput and requirements for special equipment
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Using spatially enhanced resolution omics sequencing (Stereo-seq), the study determined the spatially resolved single-cell transcriptome of axonal telencephalon slices across a range of developmental and regeneration stages
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These data allowed the researchers to identify cell types, including EGC subtypes involved in development and regeneration
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Further analysis revealed that developmental and regenerative neurogenesis share similarities in cell lineage dynamics from EGC to mature neurons and associated molecular features
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The study also observed wound-stimulating cell clusters adjacent to EGCs with neuronal regression features
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In conclusion, this work provides an overview of cellular dynamics during salamander brain development and regeneration, from which insights into the molecular regulation of brain regeneration can be gained
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